title: Identification of human IKK-2 inhibitors of natural origin (part I): modeling of the IKK-2 kinase domain, virtual screening and activity assays.
abstract: BACKGROUND
  Their large scaffold diversity and properties, such as structural complexity and drug similarity, form the basis of claims that natural products are ideal starting points for drug design and development. Consequently, there has been great interest in determining whether such molecules show biological activity toward protein targets of pharmacological relevance. One target of particular interest is hIKK-2, a serine-threonine protein kinase belonging to the IKK complex that is the primary component responsible for activating NF-κB in response to various inflammatory stimuli. Indeed, this has led to the development of synthetic ATP-competitive inhibitors for hIKK-2. Therefore, the main goals of this study were (a) to use virtual screening to identify potential hIKK-2 inhibitors of natural origin that compete with ATP and (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits.
  
  
  RESULTS
  We thus predicted that 1,061 out of the 89,425 natural products present in the studied database would inhibit hIKK-2 with good ADMET properties. Notably, when these 1,061 molecules were merged with the 98 synthetic hIKK-2 inhibitors used in this study and the resulting set was classified into ten clusters according to chemical similarity, there were three clusters that contained only natural products. Five molecules from these three clusters (for which no anti-inflammatory activity has been previously described) were then selected for in vitro activity testing, in which three out of the five molecules were shown to inhibit hIKK-2.
  
  
  CONCLUSIONS
  We demonstrated that our virtual-screening protocol was successful in identifying lead compounds for developing new inhibitors for hIKK-2, a target of great interest in medicinal chemistry. Additionally, all the tools developed during the current study (i.e., the homology model for the hIKK-2 kinase domain and the pharmacophore) will be made available to interested readers upon request.
authors.affiliation: Grup de Recerca en Nutrigenòmica, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Campus de Sescelades, Tarragona, Catalonia, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Sala
authors.forename: Laura
authors.initials: L
authors.lastname: Guasch
authors.forename: Justyna
authors.initials: J
authors.lastname: Iwaszkiewicz
authors.forename: Miquel
authors.initials: M
authors.lastname: Mulero
authors.forename: Maria-Josepa
authors.initials: MJ
authors.lastname: Salvadó
authors.forename: Montserrat
authors.initials: M
authors.lastname: Pinent
authors.forename: Vincent
authors.initials: V
authors.lastname: Zoete
authors.forename: Aurélien
authors.initials: A
authors.lastname: Grosdidier
authors.forename: Santiago
authors.initials: S
authors.lastname: Garcia-Vallvé
authors.forename: Olivier
authors.initials: O
authors.lastname: Michielin
authors.forename: Gerard
authors.initials: G
authors.lastname: Pujadas
mesh_terms: D000595:Amino Acid Sequence; D001688:Biological Products / Q000032:analysis / Q000302:isolation & purification / Q000494:pharmacology; D020134:Catalytic Domain / Q000502:physiology; D019295:Computational Biology / Q000379:methods; D057075:Enzyme Assays / Q000379:methods*; D004791:Enzyme Inhibitors / Q000302:isolation & purification* / Q000494:pharmacology; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D046609:Libraries, Digital; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary / Q000502:physiology; D015203:Reproducibility of Results; D017385:Sequence Homology; D014584:User-Computer Interface
chemical_list: D001688:Biological Products; D004791:Enzyme Inhibitors; D051550:I-kappa B Kinase